Hematopoietic signaling pathways are often regulated by tyrosine phosphorylation, which is controlled by protein tyrosine kinases (PTKs) and protein tyrosine phosphatases (PTPs). Appropriate control of protein tyrosine phosphorylation is essential for cellular homeostasis. Mutations or altered expression of PTKs or PTPs have been implicated in hematologic malignancies. Deletion of the human chromosome 20q [del(20q)] is a recurring chromosomal abnormality observed in ~10% patients with myeloproliferative neoplasms (MPNs), myelodysplastic syndrome and acute myeloid leukemia. However, the target genes within 20q associated with myeloid malignancies remain unknown. Interestingly, the PTPN1 gene is located to human chromosome 20q13, which lies within the commonly deleted region in myeloid malignancies. PTPN1 is a non-receptor protein tyrosine phosphatase, which negatively regulates JAK2. An acquired JAK2V617F mutation was identified in a large number of patients with MPNs. Interestingly, a significant proportion of del(20q) positive MPN patients also carry the JAK2V617F mutation. We have found that knockdown of PTPN1 enhances hematopoietic signaling including the JAK2/Stat5 pathway, and increases the cell growth. We also have observed that deletion of PTPN1 results in expansion of myeloid cells and enlargement of spleens in mice. We hypothesize that PTPN1 may act as a tumor suppressor in myeloid malignancies. We propose to use genetic and biochemical approaches to delineate the role of PTPN1 in myeloid malignancies. In Aim 1, using a conditional PTPN1 knockout allele, we will determine the effects of PTPN1 deletion on hematopoietic compartments. In Aim 2, we will determine if PTPN1 deficiency cooperates with JAK2V617F in myeloid malignancies. In Aim 3, we will determine the effects of PTPN1 deficiency on hematopoietic signaling and define the mechanism by which PTPN1 deficiency contributes to myeloid malignancies. These studies should provide important new insights into the role of PTPN1 in hematopoiesis and determine if PTPN1 functions as a bona fide tumor suppressor in myeloid malignancies. Results from these studies may lead to new therapeutic approach for myeloid malignancies.